title: Pretreatment of aripiprazole and minocycline, but not haloperidol, suppresses oligodendrocyte damage from interferon-γ-stimulated microglia in co-culture model.
abstract: Recent imaging studies have indicated that the pathophysiology of schizophrenia is closely related to white matter abnormalities and microglial activation. Additionally, recent clinical trials have suggested that atypical antipsychotics may have brain protective properties and that minocycline, an antibiotic with inhibitory effects on microglial activation, improves symptoms of schizophrenia. We have reported that not only atypical antipsychotics with dopamine D2 receptor (D2R) antagonism but also aripiprazole, a unique antipsychotic drug with D2R partial agonism, inhibit microglial activation in vitro. Thus, atypical antipsychotics may exert a beneficial influence on both microglia and oligodendrocytes, while the underlying mechanisms have not been clarified. Here, we investigated whether antipsychotics suppress oligodendrocyte damage by inhibiting microglial activation utilizing a co-culture model with microglia and oligodendrocytes. Pretreatment of aripiprazole and minocycline suppressed apoptosis of oligodendrocytes in the co-culture model with interferon-γ (IFN-γ)-activated microglia, while haloperidol, a traditional antipsychotic drug, did not. Aripiprazole and minocycline inhibited the production of tumor necrosis factor-alpha (TNF-α) from IFN-γ-activated microglia. Moreover, aripiprazole and minocycline attenuated the phosphorylation of signal transducer and activator of transcription 1 (STAT1) in microglia. Overall, our results suggest that aripiprazole and minocycline may have antipsychotic effects through reducing oligodendrocyte damage caused by microglial activation. These results put forward a novel therapeutic hypothesis in schizophrenia research. Future in vivo studies to confirm the present results should be performed.
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Seki
authors.forename: Takahiro A
authors.initials: TA
authors.lastname: Kato
authors.forename: Akira
authors.initials: A
authors.lastname: Monji
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Mizoguchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Horikawa
authors.forename: Mina
authors.initials: M
authors.lastname: Sato-Kasai
authors.forename: Daigo
authors.initials: D
authors.lastname: Yoshiga
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kanba
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001583:Benzoxazoles / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D008911:Minocycline / Q000494:pharmacology*; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001583:Benzoxazoles; D018991:Myelin Proteolipid Protein; D009573:Nitrites; D010879:Piperazines; D011806:Quinolinium Compounds; D015363:Quinolones; D050794:STAT1 Transcription Factor; C075296:1,1'-((4,4,7,7-tetramethyl)-4,7-diazaundecamethylene)bis-4-(3-methyl-2,3-dihydro(benzo-1,3-oxazole)-2-methylidene)quinolinium; D007371:Interferon-gamma; D000068180:Aripiprazole; D008911:Minocycline; D006220:Haloperidol
keywords: Antipsychotics; Interferon-gamma (IFN-γ); Microglia; Minocycline; Nitric oxide; Oligodendrocyte; Schizophrenia; Tumor necrosis factor-alpha (TNF-α)